Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia

Low folate intake as well as alterations in folate metabolism as a result o f polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) h ave been associated with an increased incidence of neural tube defects, vas cular disease, and some cancers. Polymorphic variants of MTHFR lead to enha nced thymidine pools and better quality DNA synthesis that could afford som e protection from the development of leukemias, particularly those with tra nslocations. We now report associations of MTHFR polymorphisms in three sub groups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemi as with MLL rearrangements and childhood lymphoblastic leukemias with eithe r TEL-AML1 fusions or hyperdiploid karyotypes, Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for M THFR polymorphisms at nucleotides 677 (C -->T) and 1,298 (A -->C). A signif icant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted od d ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.1 4). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07-0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20-1.17) were observed for hyperdiploid leukemias (n = 138). No significa nt associations were evident for either polymorphism with TEL-AML1+ leukemi as (n = 78), These differences in allelic associations may point to discret e attributes of the two alleles in their ability to alter folate and one-ca rbon metabolite pools and impact after DNA synthesis and methylation pathwa ys, but should be viewed cautiously pending larger follow-up studies, The d ata provide evidence that molecularly defined subgroups of pediatric leukem ias have different etiologies and also suggest a role of folate in the deve lopment of childhood leukemia.